Previous work has demonstrated that a brief period of cocaine exposure produces long-term functional alterations in components of the mesolimbic and nigrostriatal dopamine systems which depend on the gender of the rat. In males, postnatal day (PnD) 11-20 cocaine causes a dampening of the responsivity of the mesolimbic system primarily due to a disruption in D1-mediated cellular events. In females, the mesolimbic system appears to function normally but the nigrostriatal system does not. Gonadal hormones appear to be most significant in females since recent studies show that gonadectomy does not interact with cocaine in males while ovariectomy before cocaine administration dampens cocaine's effects in females. Aim 1 of this proposal will determine the role of ovarian hormones in producing cocaine's effects. First, the critical hormone will be identified in females and then the long term neurochemical, molecular and behavioral effects of PnD 11-20 cocaine administration in ovariectomized females will be established. Since 2DG studies show that adult males postnatally exposed to cocaine exhibit relative independence of functional components of the dopaminergic circuits, Aim 2 will examine the coupling of metabolism and behavior following amphetamine sensitization in PnD 11-20 cocaine-exposed males and females. Aim 3 will expand the scope of this work by drawing on findings from clinical studies of cocaine exposed children. Cocaine will be administered both pre and postnatally and brain metabolism and behavior will be assessed in offspring focusing on anxiety, arousal, and cognition, all previously demonstrated to be affected by either pre and/or postnatal cocaine in our lab. Together these studies will examine the neuroanatomic basis for developmental cocaine's effects on function in males and females and determine the roles of gonadal steroids in producing these effects.